MUC4 Activates HER2 Signalling and Enhances the Motility of Human Ovarian Cancer Cells

Overview

Journal Br J Cancer

Specialty Oncology

Date 2008 Jul 31

PMID 18665193

Citations 48

Authors

M P Ponnusamy

A P Singh

M Jain

S Chakraborty

N Moniaux

S K Batra

Affiliations

Soon will be listed here.

Abstract

The mucin MUC4 is a high molecular weight transmembrane glycoprotein. It consists of a mucin-type subunit (MUC4alpha) and a transmembrane growth factor-like subunit (MUC4beta). The mucin MUC4 is overexpressed in many epithelial malignancies including ovarian cancer, suggesting a possible role in the pathogenesis of these cancers. In this study, we investigated the functional role of MUC4 in the human ovarian cancer cell line SKOV3. The mucin MUC4 was ectopically expressed by stable transfection, and its expression was examined by western blot and confocal microscopy analyses. The in vitro studies demonstrated an enhanced motility of MUC4-expressing SKOV3 cells compared with the vector-transfected cells. The mucin MUC4 expression was associated with apparent changes in actin organisation, leading to the formation of microspike, lammelopodia and filopodia-like cellular projections. An enhanced protein expression and activation of HER2, a receptor tyrosine kinase, was also seen, although no significant change was observed in HER-2 transcript levels in the MUC4-transfected SKOV3 cells. Reciprocal co-immunoprecipitation revealed an interaction of MUC4 with HER2. Further, the MUC4-overexpressing SKOV3 cells exhibited an increase in the phosphorylation of focal adhesion kinase (FAK), Akt and ERK, downstream effectors of HER2. Taken together, our findings demonstrate that MUC4 plays a role in ovarian cancer cell motility, in part, by altering actin arrangement and potentiating HER2 downstream signalling in these cells.

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References

Cunningham C, Gorlin J, Kwiatkowski D, Hartwig J, Janmey P, Byers H . Actin-binding protein requirement for cortical stability and efficient locomotion. Science. 1992; 255(5042):325-7. DOI: 10.1126/science.1549777. View

Owens L, Xu L, Dent G, Yang X, Sturge G, Craven R . Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer. Ann Surg Oncol. 1996; 3(1):100-5. DOI: 10.1007/BF02409059. View

Komatsu M, Jepson S, Arango M, Carothers Carraway C, Carraway K . Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor. Oncogene. 2001; 20(4):461-70. DOI: 10.1038/sj.onc.1204106. View

Giuntoli 2nd R, Rodriguez G, Whitaker R, Dodge R, Voynow J . Mucin gene expression in ovarian cancers. Cancer Res. 1998; 58(23):5546-50. View

Andrianifahanana M, Moniaux N, Batra S . Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. Biochim Biophys Acta. 2006; 1765(2):189-222. DOI: 10.1016/j.bbcan.2006.01.002. View

Komatsu M, Tatum L, Altman N, Carothers Carraway C, Carraway K . Potentiation of metastasis by cell surface sialomucin complex (rat MUC4), a multifunctional anti-adhesive glycoprotein. Int J Cancer. 2000; 87(4):480-6. DOI: 10.1002/1097-0215(20000815)87:4<480::aid-ijc4>3.0.co;2-6. View

Schroeder J, Thompson M, GARDNER M, Gendler S . Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland. J Biol Chem. 2001; 276(16):13057-64. DOI: 10.1074/jbc.M011248200. View

Schaller M, Borgman C, Cobb B, Vines R, Reynolds A, Parsons J . pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci U S A. 1992; 89(11):5192-6. PMC: 49256. DOI: 10.1073/pnas.89.11.5192. View

Gabarra-Niecko V, Schaller M, Dunty J . FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev. 2003; 22(4):359-74. DOI: 10.1023/a:1023725029589. View

10.

Carraway K, Komatsu M, Jepson S, Perez A, Carraway C . Muc4/sialomucin complex in the mammary gland and breast cancer. J Mammary Gland Biol Neoplasia. 2001; 6(3):323-37. DOI: 10.1023/a:1011327708973. View

11.

Mitra S, Schlaepfer D . Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006; 18(5):516-23. DOI: 10.1016/j.ceb.2006.08.011. View

12.

Auersperg N, Ota T, Mitchell G . Early events in ovarian epithelial carcinogenesis: progress and problems in experimental approaches. Int J Gynecol Cancer. 2002; 12(6):691-703. DOI: 10.1046/j.1525-1438.2002.01152.x. View

13.

Moniaux N, Escande F, Porchet N, Aubert J, Batra S . Structural organization and classification of the human mucin genes. Front Biosci. 2001; 6:D1192-206. DOI: 10.2741/moniaux. View

14.

Carraway K, Carvajal M, Li P, Carraway C . ErbB2 and its ligand Muc4 (sialomucin complex) in rat lacrimal gland. Adv Exp Med Biol. 2003; 506(Pt A):289-95. DOI: 10.1007/978-1-4615-0717-8_40. View

15.

Kornberg L, Earp H, Turner C, Prockop C, Juliano R . Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. Proc Natl Acad Sci U S A. 1991; 88(19):8392-6. PMC: 52514. DOI: 10.1073/pnas.88.19.8392. View

16.

Moniaux N, Chaturvedi P, Varshney G, Meza J, Rodriguez-Sierra J, Aubert J . Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells. Br J Cancer. 2007; 97(3):345-57. PMC: 2360313. DOI: 10.1038/sj.bjc.6603868. View

17.

Komatsu M, Yee L, Carraway K . Overexpression of sialomucin complex, a rat homologue of MUC4, inhibits tumor killing by lymphokine-activated killer cells. Cancer Res. 1999; 59(9):2229-36. View

18.

Singh A, Chauhan S, Bafna S, Johansson S, Smith L, Moniaux N . Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas. Prostate. 2005; 66(4):421-9. DOI: 10.1002/pros.20372. View

19.

Hollingsworth M, Swanson B . Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2003; 4(1):45-60. DOI: 10.1038/nrc1251. View

20.

Chaturvedi P, Singh A, Moniaux N, Senapati S, Chakraborty S, Meza J . MUC4 mucin potentiates pancreatic tumor cell proliferation, survival, and invasive properties and interferes with its interaction to extracellular matrix proteins. Mol Cancer Res. 2007; 5(4):309-20. DOI: 10.1158/1541-7786.MCR-06-0353. View